β-Lactones of 2-hydroxy-cyclopentane-carboxylic acids

ABSTRACT

Novel β-lactones of 2-hydroxy-cyclopentane-carboxylic acids of the formula ##STR1## wherein R 1  is selected from the group consisting of hydrogen and methyl and R 2  is selected from the group consisting of --CH 2  --O--CH 2  --CH 3  and --X--Ar, X is selected from the group consisting of --O-- and --CH 2  --, Ar is an optionally substituted member selected from the group consisting of thienyl, thiazolyl, phenyl and thiadiazolyl, the optional substituents being at least one member selected from the group consisting of halogen and --CF 3  and the wavy lines indicate that the groups may be in the α,β or β,α-positions or mixtures thereof having hypotensive activity and their preparation.

PRIOR APPLICATION

This application is a division of our copending patent application Ser.No. 94,771 filed Nov. 16, 1979, now U.S. Pat. No. 4,264,623.

STATE OF THE ART

French Pat. No. 2,279,390, Netherlands application Serial No. 76-05856and copending commonly assigned U.S. patent application Ser. No. 036,877filed May 8, 1979 which is a continuation of application Ser. No.779,178 filed Mar. 18, 1977 describe similar compounds.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel lactones offormula I and a novel process and novel intermediates for theirpreparation.

It is another object of the invention to provide novel hypotensivecompositions and to provide a novel method of reducing blood pressure inwarm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel β-lactones of the invention are β-lactones of2-hydroxy-cyclopentane-carboxylic acids of the formula ##STR2## whereinR₁ is selected from the group consisting of hydrogen and methyl and R₂is selected from the group consisting of --CH₂ --O--CH₂ --CH₃ and--X--Ar, X is selected from the group consisting of --O-- and --CH₂ --,Ar is an optionally substituted member selected from the groupconsisting of thienyl, thiazolyl, phenyl and thiadiazolyl, the optionalsubstituents being at least one member selected from the groupconsisting of halogen and --CF₃ and the wavy lines indicate that thegroups may be in the α,β or β,α-positions or mixtures thereof.

Examples of suitable substituents on the group Ar are at least onefluorine, chlorine, bromine, iodine and/or trifluoromethyl. Among thepreferred compounds of formula I are those wherein R₂ is thien-3-yloxy,thiazol-2-yloxy, 1,2, 5-thiadiazol-3-yloxy, phenyloxy or ethoxymethyl.

Specific preferred compounds of formula I are the lactone of (1RS, 2SR,5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-1-carboxylicacid, the lactone of (1RS, 2SR, 5-RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-1-carboxylicacid, the lactone of (1RS, 2SR, 5RS, 3'RS-3'SR) (1'E)2-hydroxy-5-[3'-hydroxy-4,4'-dimethyl-6'-oxa-1'-octenyl]-cyclopentane-1-carboxylicacid, the lactone of (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid and the lactone of (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid.

The novel process of the invention for the preparation of the lactonesof formula I comprises reacting a compound of the formula ##STR3##wherein R₁ and R₂ have the above definition with a reactant selectedfrom the group consisting of tosyl chloride, alkyl chloroformates,dicycloalkylcarbodiimides, dialkylcarbodiimides and thionyl chloride toform a functional acid derivative which reacts with the hydroxyl to formthe lactone ring.

In a preferred mode of the said process, the selected reactant is tosylchloride which forms a mixed anhydride of the acid. The reaction ispreferably effected in the presence of an inorganic base such as analkali metal carbonate or an organic base such as methylmorpholine,pyridine, diazabicyclooctane or a trialkylamine such as triethylamine.Other preferred embodiments include the use of thionyl chloride or analkyl chloroformate such as isobutylchloroformate in the presence of thesaid bases.

Another process of the invention for the preparation of the compounds offormula I comprises reacting a compound of the formula ##STR4## whereinTHP is tetrahydropyranyl with a reactant for the formation of afunctional acid derivative to obtain a compound of the formula ##STR5##reacting the latter with an acid to form a compound of the formula##STR6## reacting the latter with an oxidation agent to form a compoundof the formula ##STR7## reacting the latter in the presence of a strongbase with a phosphonate of the formula ##STR8## wherein R₁ and R₂ havethe above definitions and Alk is alkyl of 1 to 4 carbon atoms to obtaina compound of the formula ##STR9## and reacting the latter with areducing agent to form the corresponding compound of formula I.

In a preferred mode of the said process, the reactant to form thefunctional acid derivative is the same as the reactant with the compoundof formula II, preferably tosyl chloride in the presence ofdiazabicyclooctane to form the mixed anhydride. The acid is preferablyoxalic acid but other acids such as hydrochloric acid, sulfuric acid oracetic acid may be used. The preferred oxidation agent is the complex ofchromic oxide in pyridine but chromic oxide in triethylamine or in acollidine may also be used. In the phosphonate of formula VII, Alk ispreferably methyl but may be other alkyls such as ethyl, propyl orbutyl. The strong base is preferably sodium hydride but other bases suchas sodium amide, sodium tert.-amylate or butyllithium may be used. Thepreferred reducing agent is zinc borohydride but other agents such assodium borohydride, sodium trismethoxyborohydride or lithiumtris(sec-butyl) borohydride may be used.

The compounds of formulae I and II contain a hydroxyl group which may bein one of 2 possible positions, either α- or β- to the carbon atom towhich it is attached, or mixtures thereof which may be separated byknown physical methods, especially chromatography. The compounds offormula I exist in the form of racemates or optical isomers and theracemates may be separated by the usual methods.

The novel intermediates products of the invention are the compounds offormula II and the compounds of the formula ##STR10## wherein R₃ isselected from the group consisting of --CH₂ OH, formyl ortetrahydropyranyloxymethyl.

The compounds of formula II may be prepared by reacting a compound ofthe formula ##STR11## wherein Alk₁ is an alkyl of 1 to 4 carbon atomswith an oxidation agent such as chromic oxide in pyridine to obtain acompound of the formula ##STR12## reacting the latter with a phosphonateof formula VII in the presence of a strong base such as sodium hydrideto obtain a compound of the formula ##STR13## reacting the latter with areducing agent such as zinc borohydride to obtain a compound of theformula ##STR14## which, if desired may be separated into its isomers,reacting the latter with an acid such as oxalic acid to obtain acompound of the formula ##STR15## reacting the latter with a reducingagent such as sodium tris (sec-butyl) borohydride to form a compound ofthe formula ##STR16## and treating the latter with first a base such assodium hydroxide and then with an acid such as dilute hydrochloric acidto form the corresponding compound of formula II.

The compounds of formula III may be made by reacting a compound of theformula ##STR17## wherein Alk₂ is alkyl of 1 to 4 carbon atoms and THPis tetrahydropyranyl with a reducing agent such as sodiumtris(sec.-butyl) borohydride to obtain a compound of the formula##STR18## and treating the latter with a base such as sodium hydroxideand then with an acid such as dilute hydrochloric acid to obtain thecorresponding compound of formula III. The compounds of formulae X andXVI are described in French Pat. No. 2,332,971.

The novel hypotensive compositions of the invention are comprised of ahypotensively effective amount of at least one compound of formula I andan inert pharmaceutical carrier or excipient. The compositions may be inthe form of tablets, dragees, gelules, granules, suppositories orinjectable solutions or suspensions.

Examples of suitable excipients are talc, arabic gum, lactose, starch,magnesium stearate, cacao butter, aqueous and non-aqueous vehicles.

Due to their hypotensive properties, the compositions are useful fortreating hypertension and circulation troubles. The preferredcompositions of the invention are those wherein R₂ is thien-3-yloxy,thiazol-2-yloxy, 1,2,5-thiadiazol-3-yloxy, phenoxy or ethoxymethyl.Especially preferred compositions are those wherein the activeingredient is selected from the group consisting of the lactone of (1RS,2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-1carboxylicacid, the lactone of (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"thienyloxy)-1'-butenyl]-cyclopentane-1-carboxylicacid, the lactone of (1RS, 2SR, 5RS, 3'RS-3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4',4'-dimethyl-6'-oxa-1'-octenyl]-cyclopentanecarboxylic acid, the lactone of (1RS, 2SR, 5RS, 3'SR)( 1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid and the lactone of (1RS, 2 SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid.

The novel method of the invention of reducing blood pressure inwarm-blooded animals comprises administering to warm-blooded animals anhypotensively effective amount of at least one compound of formula I.The compounds may be administered orally, rectally, parenterally orlocally. The usual daily dose is 0.01 to 40 mg/kg depending on thecompound and the method of administration.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 1 Lactone of (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-1-carboxylicacid STEP A: Methyl (5RS)(1'E)2-methoxy-5-[3'-oxo-4'-(3"-thienyloxy)-1'-butenyl]-1-cyclopentene-carboxylate

21 g of anhydrous chromic acid anhydride were added in small amounts at25°-30° C. to a solution of 33.7 ml of pyridine and 300 ml of methylenechloride and after the mixture stood at room temperature for 15 minutes,6.5 g of methyl (5RS)2-methoxy-5-hydroxymethyl-1-cyclopentene-carboxylate were added theretoover 10 minutes. The mixture stood at room temperature for 30 minutesand was then filtered and the filtrate was evaporated to dryness toobtain 4.5 g of an aldehyde.

6.5 g of dimethyl 2-oxo-3-(3'-thienyloxy)-propylphosphonate weredissolved in 100 ml of dimethoxyethane and 1 g of sodium hydride as a61.5% suspension in oil was added to the solution in small amounts. Theresulting suspension was allowed to stand at room temperature for 30minutes and then a solution of 4.5 g of the said aldehyde in 50 ml ofdimethoxyethane was added thereto. The reaction mixture was heated to60° C. and 10 ml of dimethylsulfoxide were added thereto. The mixturewas held at 60° C. for 90 minutes and was evaporated to dryness. Theresidue was taken up in aqueous monosodium phosphate solution and themixture was extracted with ether. The ether phase was dried overmagnesium sulfate and was evaporated to dryness. The residue waschromatographed over silica gel and was eluted with an 8-2 -ethylacetate-cyclohexane mixture to obtain 2.5 g of methyl (5RS,(1'E)2-methoxy-5-[3'-oxo-4'-(3"-thienyloxy)-1'-butenyl]-1-cyclopentene-carboxylatewith an Rf=0.4.

NMR Spectrum (CDCl₃, 60 MHz): ##STR19## (a): 3.66 p.p.m. (b): 3.89p.p.m.

(c): 3.5 to 3.92 p.p.m.

(d): 6.4 p.p.m. (doublet J: 16 MHz)

6.95 p.p.m.-7.2 p.p.m. (2 doublets J: 8 Hz)

(e): 6.25 p.p.m.

(f): 6.82 p.p.m.-6.9 p.p.m. (2 doublets J: 2 Hz)

(g): 7.24 p.p.m.-7.32 p.p.m. (2 doublets J: 3 Hz)

(h): 4.69 p.p.m.

STEP B: Methyl (5RS, 3'SR)(1'E)2-methoxy-5-[3'-hydroxy-4'-(3"thienyloxy)-1'-butenyl]-1-cyclopentene-carboxylateand methyl (5RS, 3'RS)(1'E)2-methoxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-1-cyclopentene-carboxylate

418 mg of potassium borohydride were added with stirring to a solutionof 2.5 g of the product of Step A in 50 ml of a 4-1 methanol-watermixture and after stirring the suspension for 2 hours at roomtemperature, 20 ml of an aqueous saturated monosodium phosphate solutionwere added thereto. The mixture was evaporated to dryness under reducedpressure and the residue was extracted with ethyl acetate. The organicextracts were dried and evaporated to dryness under reduced pressure andthe residue was chromatographed over silica gel. Elution with a 4-1methylene chloride-ethyl acetate mixture yielded 0.82 g of methyl (5RS,3'RS)(1'E)2-methoxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-1-cyclopentene-carboxylatewith an Rf=0.22 and 0.88 g of methyl (5RS, 3'SR)(1'E)2-methoxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-1-cyclopentene-carboxylatewith an Rf= 0.24.

IR Spectrum (CHCl₃):

Both isomers had the same IR spectrum: OH at 3579 cm⁻¹ ; conjugatedester ##STR20## at 1695 cm⁻¹ and conjugated --C═C-- at 1627 cm⁻¹ NMRSpectrum (CDCl₃ --60 MHz): ##STR21## (a): 3.7 p.p.m. (b): 3.87 p.p.m.

(c): 3.66 p.p.m.

(d): 5.33 to 6. p.p.m.

(e): 4.58 p.p.m.

(f): 3.92 p.p.m. (doublet J=6 Hz)

(g): 6.33 p.p.m.

(h): 6.83 p.p.m.

(i): 7.25 p.p.m.

STEP C: Methyl (1RS, 5RS, 3'RS)(1'E)2-oxo-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-carboxylate

820 mg of the (3'RS) isomer of Step B were dissolved with stirring in 60ml of a 1-2 methanol-water mixture and 900 mg of oxalic acid were addedthereto. The mixture was stirred at room temperature for 5 hours and wasevaporated to dryness under reduced pressure. The residue was extractedwith chloroform and the organic phase was dried and evaporated todryness under reduced pressure. The residue was chromatographed oversilica gel and was eluted with a 2-3 cyclohexane-ethyl acetate mixtureto obtain 0.6 g of methyl (1RS, 5RS, 3'RS)(1'E)2-oxo-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-carboxylatewith a Rf=0.35.

IR Spectrum (CHCl₃):

C═0 at 1802 cm⁻¹ (shoulder), at 1757 and 1732 cm⁻¹, thienyloxy at 1543cm⁻¹ and associated OH at 3567 cm⁻¹.

NMR Spectrum (CDCl₃ --60 MHz): ##STR22## (a): 3.74 p.p.m. (b): 2.99p.p.m. (double J: 11 Hz)

(c): 5.5 to 6 p.p.m.

(d): 4.38 to 4.63 p.p.m.

(e): 6.25 p.p.m.

(f): 6.76 p.p.m.

(g): 7.16 p.p.m.

(h): 3.67 to 4 p.p.m.

STEP D: Methyl (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-carboxylate

A solution of 0.6 g of the product of Step C in 15 ml of tetrahydrofurancooled to -60° C. was added over 10 minutes at -60° C. to 6.75 ml of asolution of molar L-selectride in tetrahydrofuran and the reactionmixture was stirred at -60° C. for one hour and was then poured into anaqueous saturated monosodium phosphate solution. The mixture wasextracted with ethyl acetate and the organic extracts were dried overmagnesium sulfate and evaporated to dryness under reduced pressure. Theresidue was chromatographed over silica gel and was eluted with a 4-6cyclohexane-ethyl acetate mixture to obtain 530 mg of methyl (1RS, 2SR,5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-carboxylatewith an Rf=0.2.

IR Spectrum (CHCl₃):

C═0 towards 1732-1739 cm⁻¹ and an important shoulder at 1715 cm⁻¹.

NMR Spectrum (CDCl₃ --90 MHz): ##STR23## (a): 3.72 p.p.m. (b): 2.43p.p.m.-2.48 p.p.m. (2 doublets J: 5 Hz)

(c): 5.46 to 6.05 p.p.m.

(d): 4.41 to 4.58 p.p.m.

(e): 4.41 to 4.58 p.p.m.

(f): 3.62 to 4.08 p.p.m.

(g): 6.27 to 6.34 p.p.m.

(h): 6.75 to 6.84 p.p.m.

(i): 7.14 to 7.25 p.p.m.

STEP E: (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentanecarboxylic acid

4.89 ml of 1 N sodium hydroxide solution were added all at once to amixture of 0.51 g of the product of Step D, 15 ml of water and 10 ml ofmethanol and the reaction mixture was stirred at room temperature for 3hours and was then evaporated to dryness under reduced pressure. 20 mlof water were added to the residue and the mixture was extracted withether. The aqueous phase was acidified with 1 N hydrochloric acid andwas then extracted with ethyl acetate. The organic extracts were driedand evaporated to dryness to obtain 400 mg of (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentanecarboxylic acid which was used as is for the next step.

STEP F: Lactone of (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4-(3"-thienyloxy)-1'-butenyl]-cyclopentane-1-carboxylicacid

A mixture of 600 mg of the product of Step E, 15 ml of chloroform and267 mg of tosyl chloride was stirred until dissolution and then 1.2 g ofdiazabicyclooctane was added thereto. The mixture was stirred at roomtemperature for one hour and was filtered. The filtrate was washed with1 N hydrochloric acid and the acid solution was extracted with ethylacetate. The organic extracts were dried and evaporated to dryness underreduced pressure. The residue was chromatographed over silica gel andwas eluted with a 1-1 cyclohexane-ethyl acetate mixture to obtain 130 mgof lactone (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4-(3"-thienyloxy)-1'-butenyl]-cyclopentane-1-carboxylicacid with an RF=0.4

IR Spectrum (CHCl₃):

OH at 3579 cm⁻¹ ; lactone at 1827 cm⁻¹ ; C=C at 1672-969 cm⁻¹ andconjugated thienyloxy system at 1546 cm⁻¹.

NMR Spectrum (CDCl₃ --90 MHz): ##STR24## (a): 6.75 to 6.85 p.p.m. (b):7.20 to 7.26 p.p.m.

(c): 6.30 to 6.35 p.p.m.

(d): 5.05 p.p.m. (triplet J: 4 hz)

(e): 3.15 p.p.m. (triplet J: 6 hz)

(f): 4.41 to 4.60 p.p.m.

EXAMPLE 2 Lactone of (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopropane-1-carboxylicacid STEP A: Methyl (1RS, 5RS, 3'SR)(1'E)2-oxo-5-[3'-hydroxy-4-(3"-thienyloxy)-1'-butenyl]-cyclopropane-1-carboxylate

A mixture of 880 mg of the (3'SR) isomer of Step B of Example 1, 40 mlof water, 20 ml of methanol and 900 mg of oxalic acid was stirred atroom temperature for 5 hours and the mixture was evaporated to drynessunder reduced pressure. The residue was extracted with chloroform andthe organic extracts were dried and evaporated to dryness under reducedpressure. The residue was chromatographed over silica gel and was elutedwith an 8-2 methylene chloride-ethyl acetate mixture to obtain 730 mg ofmethyl (1RS, 5RS, 3'SR)(1'E)2-oxo-5-[3'-hydroxy-4-(3"-thienyloxy)-1'-butenyl]-cyclopropane-1-carboxylatewith an RF=0.35. The product had the same constants as itsdiastereoisomer of Step C of Example 1.

STEP B: Methyl (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-carboxylate

A solution of 0.365 g of the product of Step A in 10 ml of thetetrahydrofuran was added over 10 minutes at -60° C. to 4.1 ml of amolar solution of L-selectride in tetrahydrofuran and the mixture wasstirred at -60° C. for one hour and was then poured into an aqueoussaturated monosodium phosphate solution. The mixture was extracted withethyl acetate and the organic extracts were dried and evaporated todryness under reduced pressure. The residue was chromatographed oversilica gel and was eluted with a 4-6 cyclohexane-ethyl acetate mixtureto obtain 230 mg of methyl (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-carboxylatewith an Rf=0.2. Its constants were the same as its diastereoisomer ofStep D of Example 1.

STEP C: (1RS, 2SR, 5RS, 3'SR)(1'E) 2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-carboxylicacid

A mixture of 0.23 g of the product of Step B, 10 ml of water and 6 ml ofmethanol was stirred while 2.2 ml of 1 N sodium hydroxide solution wasadded thereto all at once and the mixture was stirred at roomtemperature for 3 hours and was evaporated to dryness. 20 ml of waterwere added to the residue and the mixture was washed 3 times with etherand was acidified with 1 N hydrochloric acid. The aqueous phase wasextracted with ethyl acetate and the organic phase was dried andevaporated to dryness to obtain 400 mg of (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-carboxylicacid.

STEP D: Lactone of (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-1-carboxylicacid

A mixture of 197 mg of the product of Step C, 10 ml of chloroform and131.7 mg of tosyl chloride was stirred until dissolution occured and0.592 g of diazabicyclooctane was added thereto. The mixture was stirredat room temperature for one hour and was vacuum filtered. The filtratewas washed with 1 N hydrochloric acid and the acid solution wasextracted with ether. The combined ether phases were dried andevaporated to dryness under reduced pressure. The residue waschromatographed over silica gel and was eluted with a 7-3 methylenechloride-ethyl acetate mixture to obtain 100 mg of lactone of (1RS, 2SR,5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-(3"-thienyloxy)-1'-butenyl]-cyclopentane-1-carboxylicacid with an Rf=0.45.

IR Spectrum (CHCl₃):

OH at 3579 cm⁻¹ ; β-lactam at 1827 cm⁻¹ ; C═C at 1672-969 cm⁻¹ ;conjugated thienyloxy system at 1546 cm⁻¹.

NMR Spectrum (CDCl₃ --90 MHz): ##STR25## (a): 6.75 to 6.85 p.p.m. (b):7.20 to 7.26 p.p.m.

(c): 6.30 to 6.35 p.p.m.

(d): 5.05 p.p.m.

(e): 3.15 p.p.m.

(f): 5.4 to 5.92 p.p.m.

(g): 4.4 to 4.6 p.p.m.

EXAMPLE 3 Lactone of (1RS, 2SR, 5SR, 3'RS-SR)(1'E)2-hydroxy-5-[3'-hydroxy-4',4'-dimethyl-6'-oxa-1'-octenyl]-cyclopentanecarboxylic acid STEP A: Methyl (1RS, 2SR, 5SR)2-hydroxy-5-(α-tetrahydropyranyloxy)-methyl-cyclopentane-carboxylate

A solution of 7 g of methyl (1RS, 5SR)2-oxo-5-(α-tetrahydropyranyloxy)-methyl-cyclopentane-carboxylate in 50ml of tetrahydrofuran was added dropwise with stirring to 100 ml ofL-selectride cooled to -70° C. and the mixture was stirred at -70° C.for 90 minutes. The mixture was poured into an iced aqueous saturatedmonosodium phosphate solution and the mixture was extracted with ethylacetate. The extracts were dried and evaporated to dryness and theresidue was chromatographed over silica gel. Elution with a 1-1cyclohexane-ethyl acetate mixture yielded 3.925 g of methyl (1RS, 2SR,5SR) 2-hydroxy-5-(α-tetrahydropyranyloxy)-methylcyclopentane-carboxylate with an Rf=0.18.

IR Spectrum (CHCl₃):

C═0 at 1739-1715 cm⁻¹

NMR Spectrum (CDCl₃ --60 MHz): ##STR26## (a): 2.67 p.p.m. (b): 4.45p.p.m.

(c) (e): 3.17 to 4.17 p.p.m.

(d): 4.6 p.p.m.

(f): 3.74 p.p.m.-3.66 p.p.m.

STEP B: (1RS, 2SR, 5SR)2-hydroxy-5-(α-tetrahydropyranyloxy)methylcyclopentane carboxylic acid

15.1 ml of 2 N sodium hydroxide solution were added under an inertatmosphere to a solution of 3.9 g of the product of Step A in 40 ml ofmethanol and the mixture was stirred at room temperature for 6 hours.The mixture was poured into water and the mixture was acidified withmonosodium phosphate. The mixture was extracted with ethyl acetate. Theextracts were dried and evaporated to dryness to obtain 3.626 g of (1RS,2SR, 5SR) 2-hydroxy-5-(α-tetrahydropyranyloxy)-methylcyclopentanecarboxylic acid.

IR Spectrum (CHCl₃):

COOH at 1737 cm⁻¹

STEP C: Lactone of (1RS, 2SR, 5SR)2-hydroxy-5-(α-tetrahydropyranyloxy)-methylcyclopentane carboxylic acid

6.43 g of diazabicyclooctane and 3.277 g of tosyl chloride were added toa solution of 3.5 g of (1RS, 2SR, 5SR)2-hydroxy-5-(α-tetrahydropyranyloxy)-methylcyclopentane carboxylic acidin 70 ml of chloroform and the resulting solution was stirred under aninert atmosphere for 21/2 hours and was then poured in an aqueoussaturated monosodium phosphate solution. The mixture was extracted withchloroform and the organic phase was washed with water, dried andevaporated to dryness. The residue was chromatographed over silica geland was eluted with a 6-4 cyclohexane-ethyl acetate mixture to obtain1.694 g of lactone of (1RS, 2SR, 5SR)2-hydroxy-5-(α-tetrahydropyranyloxy)-methylcyclopentane carboxylic acid.

IR Spectrum (CHCl₃):

C═0 at 1818 cm⁻¹ complex

RMN Spectrum (CDCl₃ --60 MHz): ##STR27## (a): 3.88 p.p.m. (triplet J=3Hz) (b): 5.02 p.p.m. (triplet J=3 Hz)

(c) (e) 3 to 4. p.p.m.

(d): 4.55 p.p.m.

STEP D: Lactone of (1RS, 2SR, 5SR)2-hydroxy-5-hydroxymethylcyclopentane-carboxylic acid

555 mg of oxalic acid were added to a solution of 1.66 g of the productof Step C, 32 ml of ethanol and 3.2 ml of water and the reaction mixturewas heated under an inert atmosphere for 41/2 hours and was evaporatedto dryness. The residue was taken up in water and the aqueous phase wasextracted with chloroform. The organic phase was dried and evaporated todryness under reduced pressure. The residue was chromatographed oversilica gel and was eluted with a 4-6 cyclohexane-ethyl acetate mixtureto obtain 542 mg of lactone of (1RS, 2SR, 5SR)2-hydroxy-5-hydroxymethyl-cyclopentanecarboxylic acid with an Rf=0.14.

IR Spectrum (CHCl₃):

Presence of OH and β-lactam

NMR Spectrum (CDCl₃ --60 MHz): ##STR28## (a): 3.90 p.p.m. (doublet J:3.5 Hz) (b): 5.03 p.p.m. (triplet J: 3.5 Hz)

(c): 1.5 to 2.83 p.p.m.

(d): 3.45 p.p.m.

STEP E: Lactone of (1RS, 2SR, 5RS)(1'E)2-hydroxy-5-(3'-oxo-4',4'-dimethyl-6'-oxa-1'-octenyl)-cyclopentane-carboxylicacid

3.4 ml of pyridine and 2.11 g of chromic acid anhydride were added insmall fractions with stirring to 60 ml of methylene chloride and themixture was stirred for 30 minutes at room temperature. A solution of500 mg of the product of Step D in 2 ml of methylene chloride was addedthereto and the mixture was stirred at room temperature for 30 minutesand was filtered. The filtrate was evaporated to dryness to obtain 1.070g of aldehyde.

A solution of 1.064 g of dimethyl2-oxo-3,3-dimethyl-5-oxa-heptanyl-phosphonate in 12 ml ofdimethoxyethane was added with stirring to a suspension of 202 mg ofsodium hydride in 50% oil suspension and 12 ml of dimethoxyethane. Themixture was stirred for one hour at room temperature and after coolingthe solution to -35° C., a solution of 1.070 g of said aldehyde in 12 mlof dimethoxyethane was added thereto over 20 minutes. The mixture wasstirred for 30 minutes and was then poured into an aqueous saturatedmonosodium phosphate solution. The mixture was extracted with ethylacetate and the organic phase was dried over magnesium sulfate andevaporated to dryness. The residue was chromatographed over silica geland was eluted with a 7-3 cyclohexane-ethyl acetate mixture to obtain394 mg of lactone of (1RS, 2SR, 5RS)(1'E)2-hydroxy-5-(3'-oxo-4',4'-dimethyl-6'-oxa-1'-octenyl)-cyclopentane-carboxyliccacid with an Rf=0.4.

IR Spectrum (CHCl₃):

lactone at 1828 cm⁻¹ ; shoulder at 1810 cm⁻¹ ; conjugated ketone at1693-1626 cm⁻¹.

NMR Spectrum (CDCl₃ --60 MHz) ##STR29## (a): 3.84 p.p.m. (doublet J=5Hz) (b): 5.05 p.p.m. (triplet J=3 Hz)

(c): 6.77 p.p.m. (doublet J=5 Hz)

(d): 6.42 p.p.m. (doublet J=4 Hz)

(e): 1.13 p.p.m.

(f): 3.42 p.p.m.

(g): 3.46 p.p.m. (quadruplet J: 7 Hz)

(h): 1.13 p.p.m. (triplet J: 7 Hz)

STEP F: Lactone [1R, 2SR, 5RS, 3'(SR-RS)](1'E)2-hydroxy-5-(3'-hydroxy-4',4'-dimethyl-6'-oxa-1'-octenyl)-cyclopentanecarboxylic acid

2.9 ml of a 0.4 molar zinc borohydride solution were added dropwise at0° C. to a solution of 392 mg of the product of Step E in 21.5 ml ofdimethoxyethane and after the temperature returned to room temperature,the mixture was stirred for 2 hours and then was poured into an aqueoussaturated monosodium phosphate solution. The mixture was extracted withethyl acetate and the organic phase was dried and evaporated to dryness.The residue was chromatographed over silica gel and was eluted with a6-4 cyclohexane-ethyl acetate mixture to obtain 251 mg of lactone of[1RS, 2SR, 5RS, 3'(SR-RS)](1'E)2-hydroxy-5-(3'-hydroxy-4',4'-dimethyl-6'-oxa-1'-octenyl)-cyclopentanecarboxylic acid with an Rf=0.26.

IR Spectrum (CHCl₃):

C═0 at 1822 cm⁻¹ ; shoulder at 1806 cm⁻¹ ; C═C at 1668 cm⁻¹ and 973 cm⁻¹; free OH at 3610 cm⁻¹ ; associated OH at 3448 cm⁻¹

NMR Spectrum (CDCl₃ --60 MHz): ##STR30## (a) (f): 3.83 p.p.m. (b): 5.05p.p.m. (triplet J: 3 Hz)

(c): 1.5 to 2.33 p.p.m.

(d): 3.17 p.p.m.

(e): 5.53 p.p.m.

(g): 0.87 p.p.m.

(h): 3.28 p.p.m.

(i): 3.47 p.p.m. (quadruplet J: 7 Hz)

(j): 1.18 p.p.m. (triplet J: 7 Hz)

EXAMPLE 4 Lactone of (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid STEP A: Methyl (5RS)(1'E)2-methoxy-5-[3'-oxo-4'-phenoxy-1'-butenyl]-1-cyclopentene-carboxylate

65 mg of sodium hydride as a 60% mineral oil suspension were slowlyadded under an inert atmosphere with stirring to 5 ml ofdimethoxy-ethane and a solution of 413 mg of dimethyl2-oxo-3-(3'-phenoxy)-propyl phosphate in 5 ml of dimethoxyethane wereadded thereto. The mixture was stirred for 2 hours at 20° C. and asolution of 290 mg of methyl (RS)2-methoxy-5-formyl-1-cyclopentene-carboxylate in 5 ml of dimethoxyethanewas added to the suspension. The mixture was stirred at 20° C. for 24hours and was then poured into an iced aqueous saturated monosodiumphosphate solution. The mixture was extracted with ethyl acetate and theorganic phase was washed with water, dried and evaporated to dryness.The residue was chromatographed over silica gel and was eluted with a1--1 cyclohexane-ethyl acetate mixture containing 0.2% of triethylamineto obtain 174 mg of methyl (5RS)(1'E) 2-methoxy-5-[3'-oxo-4'-phenoxy-1'-butenyl]-1-cyclopentene-carboxylate which aftercrystallization from an isopropyl ether-ether mixture melted at 90° C.

STEP B: Methyl (5RS, 3'RS)(1'E)2-methoxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-1-cyclopentene-carboxylateand methyl (5RS, 3'SR)(1'E)2-methoxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-1-cyclopentene-carboxylate

Using the procedure of Step B of Example 1, 392 mg of the product ofStep B were reacted and the residue was chromatographed over silica gel.Elution with a 9-1 methylene chloride-ethyl acetate mixture containing0.1% of triethylamine yielded 110 mg of methyl (5RS, 3'RS)(1'E)2-methoxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-1-cyclopentene-carboxylatewith an Rf=0.35 and 130 mg of methyl (5RS, 3'SR) (1'E)2-methoxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-1-cyclopentene-carboxylatewith an Rf=0.40.

STEP C: Methyl (1RS, 5RS, 3'RS)(1'E)2-oxo-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane carboxylate

Using the procedure of Step C of Example 1, 110 mg of the (3'RS) isomerof Step B were reacted and the residue was chromatographed over silicagel. Elution with an 85-15 methylene chloride-ethyl acetate mixtureyielded 84 mg of methyl (1RS, 5RS, 3'RS)(1'E)2-oxo-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane carboxylate withan Rf=0.35.

STEP D: Methyl (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-carboxylate

Using the procedure of Step D of Example 1, 116 mg of the product ofStep C were reacted and the residue was chromatographed over silica gel.Elution with an 85-15 methylene chloride-ethyl acetate mixture yielded85 mg of methyl (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-carboxylatewith an Rf=0.13 and which melted at 109° C. after crystallization froman ether-isopropyl ether mixture.

STEP E: (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4-phenoxy-1'-butenyl]-cyclopentene carboxylicacid

Using the procedure of Step E of Example 1, 85 mg of the product of StepD were reacted to obtain 71 mg of (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane carboxylicacid melting at 146° C.

STEP F: Lactone of (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid

Using the procedure of Step F of Example 1, 71 mg of the product of StepE were reacted and the residue was chromatographed over silica gel.Elution with a 95-5 methylene chloride-ethyl acetate mixture yielded 42mg of lactone of (1RS, 2SR, 5RS, 3'RS)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid with an Rf=0.25 and a melting point of 83° C.

IR Spectrum (CHCl₃):

OH at 3580 cm⁻¹ ; lactone at 1821 cm⁻¹ ; C═C at 968 cm⁻¹ ; aromaticbonds at 1598-1586-1495 cm⁻¹

NMR Spectrum (CDCl₃ --90 MHz): ##STR31## (a): 4.53 to 4.96 p.p.m. (b):3.53 to 3.99 p.p.m.

(c): 3.31-3.35 and 3.39 p.p.m.

(d): 2.99 p.p.m. (multiplet)

(e): 2.43 to 2.74 p.p.m.

(f): 2.09 p.p.m.

EXAMPLE 5 Lactone of (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid STEP A: Methyl (1RS, 5RS, 3'SR)(1'E)2-oxo-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-carboxylate

Using the procedure of Step A of Example 2, the (3'SR) of Step B ofExample 4 was reacted and the residue was chromatographed over silicagel. Elution with an 8-2 methylene chloride-ethyl acetate mixtureyielded methyl (1RS, 5RS, 3'SR)(1'E)2-oxo-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-carboxylate withan Rf=0.35.

STEP B: Methyl (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-carboxylate

Using the procedure of Step B of Example 2, the product of Step A wasreacted and the residue was chromatographed over silica gel. Elutionwith a 4-6 cyclohexane-ethyl acetate mixture yielded (1RS, 2SR, 5RS,3'SR)(1'E)2-hydroxy-5'[3'-hydroxy-4'-phenoxy-1'-butenyl-cyclopentanecarboxylatewith an Rf=0.2.

STEP C: (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-carboxylicacid

Using the procedure of Step C of Example 2, the product of Step B wasreacted to obtain (1RS, 2SR, 5RS, 3'SR) (1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-carboxylicacid.

STEP D: Lactone of (1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid

Using the procedure of Step D of Example 2, the product of Step C wasreacted and the residue was chromatographed over silica gel. Elutionwith a 95-5 methylene chloride-ethyl acetate mixture yielded lactone of(1RS, 2SR, 5RS, 3'SR)(1'E)2-hydroxy-5-[3'-hydroxy-4'-phenoxy-1'-butenyl]-cyclopentane-1-carboxylicacid with an Rf=0.25 and a melting point of 90° C.

EXAMPLE 6

Gelules were prepared containing 1 mg or 5 mg of the product of Example1 and sufficient excipient for a final weight of 400 mg. Injectablesolutions were also prepared with 1 mg or 5 mg of the product of Example2 and sufficient sterile water for a final volume of 5 ml.

PHARMACOLOGICAL DATA

A. Hypotensive activity in rabbits

The products were administered as a solution in physiological serumcontaining 10% of ethanol intraveinously to rabbits anesthetized withurethane. The carotidine pressure was measured and the dose whichlowered the pressure by 30% was 50 μg/kg for the product of example 1,<30 μg/kg for the product of example 2, <20 μg/kg for the product ofexample 4 and 10 μg/kg for the product of example 5.

B. Hypotensive activity in Dogs

Adult bastard dogs of both sexes weighing 14 to 20 kg with a closedthorax were anesthetized with a barbiturate mixture. The traechas wasintubed and the animals were artifically ventilated with a pump. Thearterial pressure of the carotide was ascertained with a pressure headand the dose which reduced the arterial pressure by 20% for at least 20minutes was determined to be 1 mg/kg for the product of Example 2.

Various modifications of the products and processes of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is to be limited only as defined in theappended claims.

We claim:
 1. A compound having the formula ##STR32## wherein R₃ isselected from the group consisting of CH₂ --OH, formyl andα-tetrahydropyranyloxymethyl.
 2. A compound of claim 1 wherein R₃ is--CH₂ --OH.
 3. A compound of claim 1 wherein R₃ is formyl.
 4. A compoundof claim 1 wherein R₃ is α-tetrahydropyranyloxymethyl.